Therapeutic and diagnostic applications of nanofabrication technology are gaining increasing interest. Over the past several decades almost all efforts in controlled release drug delivery has been focused on polymer-based, diffusion/degradation-controlled delivery strategies. Current “controlled release” drug delivery systems are based primarily on particles or matrices of various polymers and lipids where the release of the therapeutic agent is controlled primarily by diffusion and hydrolytic degradation. Although progress has been made and several new products are coming in the market that can significantly enhance patient compliance, reduce side effects, and improve the quality of life, there remain several limitations of these approaches.
First, despite the development of sophisticated and sensitive assays to study drug release and polymer degradation in vitro, little correlation exists between in vitro observations and in vivo performance of diffusion/degradation controlled devices. The effects of tissue environments in vivo, especially tissue pH, enzymes, salt concentrations, and the rarity with which perfect sink conditions are met, makes most prediction of drug diffusion/release inherently inaccurate.
Second, delivery systems that rely on particle-based strategies, e.g., micro and nanoparticles for tissue targeted delivery, suffer from the limitation that the bottom-up synthesis processes produce a large polydisperse population of particles whose physico-chemcial characteristics, drug release profiles, degradation kinetics, and material properties become hard to evaluate and reproduce, especially at pharmaceutical scales.
Third, the lack of a stimuli-responsive release mechanism results in the release of the drug in a somewhat uncontrolled manner, which often results in systemic side effects.
Fourth, particle-based drug carriers rely on emulsion or micelle formation for synthesis and drug loading, thereby achieving only limited and often poor encapsulation efficiency. This limitation becomes particularly critical of highly expensive and difficult to synthesize drugs, leading to limited application and high cost. Strategies to enhance drug entrapment within carriers would therefore be highly beneficial.
Fifth, combining multiple functionalities (i.e., both targeting as well as stimuli-sensitive properties), in a controlled and reproducible manner is significantly difficult in self-assembled carrier systems. Polymer-based pro-drugs offer the closest design to such combinatorial approach (Ulbrich et al., J. Control Release 2000, 64:63-79; Peterson et al., Adv. Exp. Med. Biol. 2003, 519:101-23; Ulbrich et al., J Control Release 2003, 87:33-47; Ulbrich and Subr, Adv. Drug Deliv. Rev. 2004, 56:023-50; Rihova et al., J. Control Release 2000, 64:41-61; Kovar et al., J. Control Release 2004, 99:301-14; Kopecek et al., Eur. J. Pharm. Biopharm. 2000, 50:61-81). However, such designs do not allow for simultaneous delivery of multiple agents (drugs, contrast agents etc.) and are yet to have demonstrated conclusive clinical efficacy. Newer approaches in delivery of therapeutics are therefore urgently needed.
A key issue in drug delivery is disease-responsive release. Despite current efforts to target drug nanoparticles and liposomal drug carriers to diseased cells in vivo (Kreuter, J. Nanosci. Nanotechnol. 2004, 4:484-8; Park et al., Adv. Pharmacol. 1997, 40:399-435; Park et al., Semin. Oncol. 2004, 31:196-205; Noble et al., Expert Opin. Ther. Targets 2004, 8:335-53), it is inevitable that during transport to target cells and the extracellular residence time, significant amounts of toxic drugs will diffuse to normal tissues. A combination of both cellular targeting and disease-specific, stimuli responsive delivery would provide a significantly improved design. Although several concepts have been proposed to address the issues of stimuli responsiveness (Peppas et al., Eur. J. Pharm. Biopharm. 2000, 50:27-46; Miyata et al., Adv. Drug Deliv. Rev. 2002, 54:79-98; Qiu and Park, Adv. Drug Deliv. Rev. 2001, 53:321-39) and tissue targeting (Park et al., 1997, supra; Park et al., 2004, supra; Ulbrich et al., 2000, supra; Lu et al., J. Control Release 2002, 78:165-73), the inherent complexity of bottom-up (i.e. self-assembly) synthetic approaches (e.g., emulsions or micelles) makes it difficult to incorporate both these functionalities in a single delivery platform. A top-down nanomachining approach that would ensure triggered bolus release of drugs, primarily in response to a specific stimulus, from a highly monodisperse population of carriers could provide significantly improved alternatives to currently available diffusion/hydrolysis controlled systems.